Valfix Mechanism of Action

Pharmacology: Pharmacodynamics: 100 mg: Lamivudine is an antiviral agent which is highly active against hepatitis B virus (HBV) in all cell lines tested and in experimentally infected animals.
Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative which is the active form of the parent compound. The intracellular half-life of the triphosphate in hepatocytes is 17-19 hrs in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase. The formation of further viral DNA is blocked by incorporation of lamivudine-TP into the chain and subsequent chain termination.
Lamivudine-TP does not interfere with normal cellular deoxynucleotide metabolism. It is also only a weak inhibitor of mammalian DNA polymerases α and β. Furthermore, lamivudine-TP has little effect on mammalian cell DNA content.
In assays relating to potential drug effects on mitochondrial structure and DNA content and function, lamivudine lacked appreciable toxic effects. It has a very low potential to decrease mitochondrial DNA content, is not permanently incorporated into mitochondrial DNA and does not act as an inhibitor of mitochondrial DNA polymerase γ.
150 mg: Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5'-triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication in vitro, it is also active against zidovudine-resistant clinical isolates of HIV. No antagonistic effects in vitro were seen with lamivudine and other anti retrovirals (tested agents: abacavir, didanosine, nevirapine and zidovudine).
Pharmacokinetics: Absorption: Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral lamivudine in adults is normally between 80-85%. Following oral administration, the mean time (t_max) to maximal serum concentrations (C_max) is about an hour.
100 mg: At therapeutic dose levels ie. 100mg once daily, C_max is in the order of 1.1-1.5 mcg/ml and trough levels were 0.015-0.02mcg/ml.
Co-administration of lamivudine with food resulted in a delay of t_max and a lower C_max (decreased by up to 47%). However, the extent (based on the AUC) of lamivudine absorbed was not influenced, therefore lamivudine can be administered with or without food.
150 mg: Co-administration of lamivudine with food results in a delay of t_max and a lower C_max. However, the extend (based on the AUC) of lamivudine absorbed is not influenced.
Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Distribution: 100 mg: From IV studies, the mean volume of distribution is 1.3L/kg.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein-binding to albumin.
Limited data shows lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF).
The mean lamivudine CSF/serum concentration ratio 2-4 hrs after oral administration was approximately 0.12.
150 mg: The mean volume of distribution is 1.3 l/kg. The observed half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (> 70%) via the organic cationic transport system.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin.
Metabolism: 100 mg: Lamivudine is predominantly cleared by renal excretion of unchanged drug. The likelihood of metabolic drug interactions with lamivudine is low due to the small (5-10%) extent of hepatic metabolism and the low plasma protein-binding.
Elimination: 100 mg: The mean systemic clearance of lamivudine is approximately 0.3L/hr/kg. The observed elimination half-life is 5-7 hrs. The majority of lamivudine is excreted unchanged in the urine via glomerular filtration and active secretion (organic cationic transport system).
Renal clearance accounts for about 70% of lamivudine elimination.
150 mg: Lamivudine elimination is affected by renal dysfunction. A recommended dosage regimen for patients with creatinine clearance below 50 ml/min is shown in the Dosage & Administration.
Biotransformation: 150 mg: The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell (16 to 19 hours) compared to the plasma lamivudine half-life (5 to 7 hours).
Lamivudine is predominantly cleared unchanged by renal excretion. The likelihood of metabolic interactions of lamivudine with other medicinal products is low due to the small extent of hepatic metabolism (5-10%) and low plasma protein binding.
Special populations: 100 mg: Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction in patients with a creatinine clearance of <50mL/min is necessary.
A study in hepatically impaired patients (non-HIV and non-HBV infected) showed lamivudine is well tolerated in this patient group with no changes in laboratory parameter or the adverse event profile of lamivudine. The pharmacokinetics of lamivudine are unaffected by hepatic impairment.
Limited data in patients undergoing liver transplantation show that impairment of hepatic function does not impact significantly on the pharmacokinetics of lamivudine unless accompanied by renal dysfunction.
In elderly patients, the pharmacokinetics profile of lamivudine suggests that normal ageing with accompanying renal decline has no clinically significant effect on lamivudine exposure, except in patients with creatinine clearance of <50mL/min.
Following oral administration, lamivudine pharmacokinetics in late pregnancy were similar to non-pregnant adults.